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Autophagy. 2018;14(7):1280-1282. doi: 10.1080/15548627.2018.1462079. Epub 2018 Jul 20.

Phasing out the bad-How SQSTM1/p62 sequesters ubiquitinated proteins for degradation by autophagy.

Author information

1
a Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories (MFPL), Vienna Biocenter (VBC) , University of Vienna , Vienna , Austria.
2
b Structural and Computational Biology Unit , European Molecular Biology Laboratory , Heidelberg , Germany.
3
c Department of Structural and Computational Biology, Max F. Perutz Laboratories (MFPL), Vienna Biocenter (VBC) , University of Vienna , Vienna , Austria.

Abstract

The degradation of misfolded, ubiquitinated proteins is essential for cellular homeostasis. These proteins are primarily degraded by the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy serves as a backup mechanism when the UPS is overloaded. How autophagy and the UPS are coordinated is not fully understood. During the autophagy of misfolded, ubiquitinated proteins, referred to as aggrephagy, substrate proteins are clustered into larger structures in a SQSTM1/p62-dependent manner before they are sequestered by phagophores, the precursors to autophagosomes. We have recently shown that SQSTM1/p62 and ubiquitinated proteins spontaneously phase separate into micrometer-sized clusters in vitro. This enabled us to characterize the properties of the ubiquitin-positive substrates that are necessary for the SQSTM1/p62-mediated cluster formation. Our results suggest that aggrephagy is triggered by the accumulation of substrates with multiple ubiquitin chains and that the process can be inhibited by active proteasomes.

KEYWORDS:

LC3; Selective autophagy; aggrephagy; cargo receptor; p62; phase transition; quality control; ubiquitin

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